The immune response to cancer is marked by inadequate activation of immune cells and their poor targeting of tumors. This is very much the case with glioblastoma (GBM), the most common and lethal primary brain tumor. This proposal aims to tackle both issues with novel immunoconjugates designed to simultaneously activate circulating natural killer (NK) cells while also linking them to tumor blood vessels or directly to cancer cells. Each of these leukocyte-endothelial/cancer crosslinkers (LECCs) consists of two biotinylated antibodies conjugated by an avidin; half the antibodies bind either the activating NKG2D or CD16 receptors on NK cells and the other half bind to the ?v?3 integrin expressed on both tumor vascular endothelial cells and many cancer cells. The conjugates are extremely stable and easy to synthesize in the laboratory. Our preliminary data already indicate promising activity of the NK LECC. This proposal will test the ability of the NK LECC in vitro to trigger NK cell binding and killing of GBM cells and GBM endothelial cells, as well as its in vivo biological effects and efficacy. Successful completion of the proposed work should yield a novel and easily translatable immunotherapy with activity not only against GBM but potentially against most cancers. Furthermore, this approach can easily be extended to recruit other leukocyte types and target other markers on tumor vasculature and cancer cells.